The present invention, in some embodiments thereof, relates to compositions and methods for treating cancer resistant to a tyrosine kinase inhibitor.
The ErbB/HER family of receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR, also termed ErbB-1, HER1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4) is widely known and researched. The ErbB/HER family members and their multiple ligand molecules form a layered signaling network, which is implicated in several human cancers. ErbB activation leads to downstream stimulation of several signaling cascades, including MAPK and PI(3)K/Akt that influence cell proliferation, angiogenesis, invasion and metastasis [Citri and Yarden Nat Rev Mol Cell Biol. (2006) 7(7):505-16]. Because of their oncogenic potential and accessibility, ErbB/HER proteins have emerged as attractive targets for pharmaceutical interventions. Consistently, strategies able to interfere with ErbB functions, such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have yielded in the last decade several oncology drugs which have shown great success in treating many patients with lung, breast, colon and other types of cancer.
For example, the anti-EGFR mAbs cetuximab (ERBITUX®) and the anti-HER2 mAb trastuzumab (HERCEPTIN®) have been developed and approved for the treatment of human cancers.
TKIs are small-molecule therapeutics designed to bind to the ATP-binding site of the tyrosine kinase domain, preempting the binding of ATP and directly inhibiting the kinase activity of ErbB receptors such as EGFR or HER2. For example, a number of TKIs for EGFR have been developed; including gefitinib (IRESSA®) and erlotinib (TARCEVA®), both gained FDA approval in oncology treatment. In addition, TKIs that simultaneously target multiple ErbB species, such as AZD9291, CI-1033 (PD183805) and lapatinib (GW572016/TYKERB®), have also been developed.
However, while many cancer patients were found to be sensitive to ErbB-targeted therapy, many other patients are resistant to treatment, and even among the initially responsive patients a large percentage experience tumor recurrence and become refractory to therapy. Thus for example, despite initial dramatic response of non-small cell lung cancer (NSCLC) patients to TKIs, all patients acquire resistance within approximately one year (6, 7). The most common (>50%) mechanism of this acquired resistance involves a specific second site mutation in the EGFR kinase domain. A threonine-to-methionine substitution at position 790 creates a steric hindrance that limits the binding of the TKIs, while preserving the kinase activity. [Wang and Greene J Clin Invest. (2008) 118(7): 2389-2392]. Amplification of the gene encoding another receptor tyrosine kinase, MET, occurs in 5-10% of cases of acquired resistance (11, 12).
To overcome TKI resistance, several second and third generation TKIs are being developed (13,14). Alternatively, a clinical trial combining cetuximab and chemotherapy (cis-platin/vinorelbin) demonstrated a relatively small, but significant increase in patient survival (15).
The cooperative role of the ErbB family members has furthermore been supported by in-vitro and in-vivo studies demonstrating that resistance to both mAbs and TKIs targeting a specific ErbB is associated with dysregulation and increased activity of other ErbB family members (see e.g. Wheeler et al. Oncogene. Jun. 26, 2008; 27(28): 3944-3956; Takezawa et al. Cancer discovery (2012) 2, 922-933 and Sergina et al. Nature (2007) 445, 437-441]. Thus, methods for overcoming resistance to an ErbB pathway inhibitor using combinations of ErbB family inhibitors were also described in the art for e.g. breast, lung, head and neck cancers. For example, International Application Publication No. WO 2012/125864 discloses the use of an ErbB-3 inhibitor and a second ErbB pathway inhibitor, the ErbB-3 inhibitor may be a bi-specific antibody which also targets ErbB-2 in order to overcome acquired resistance to the small molecule EGFR inhibitor gefitinib.
Other art documents related to antibody combinations in the treatment of cancer resistance to an ErbB-targeted therapy include:
US Patent Application Publication Number: 20100016296;
International Application Publication Numbers: WO 2012/059857;
Sarup et al. [Mol. Canc. Ther. (2008) 7(10):3223-3236];
Ma et al. [Molecular Cancer 2014, 13:105];
Jiang et al. [Chemother Res Pract. 2012; 2012:817304];
Wheeler et al. [Oncogene. (2008) 27(28): 3944-3956];
Rexer et al. Clin Cancer Res. (2013) 19(19):5390-401]; and
Takezawa et al. [Cancer discovery (2012) 2, 922-933].